Our previous research demonstrated that the genetic marker, "apolipoprotein type 4 allele" (APOE-4) is correlated with the increased risk of Alzheimer's Disease (AD). While a variety of neuropsychological and functional imaging tests has been demonstrated to predict subsequent cognitive decline, such studies are unlikely to identify very early abnormalities because they: (1) assess brain function during a "resting" state when mental activity is poorly controlled and the specific mental processes showing impairment are not activated; (2) often include subjects without genetic risk for subsequent decline; and, most importantly (3) emphasize measures sensitive only to advanced disease and substantial neuronal loss. In the research proposed here, we aim to study functional Magnetic Resonance Imaging (fMRI) during cognitive activation tasks in a cohort of individuals genetically at-risk for AD. We hypothesize that, prior to the appearance of overt neuropsychological decline, the early processes of neuronal dysfunction will have resulted in compensatory cognitive strategies such that the pattern of neuronal activation will differ in those individuals who will later develop more severe functional losses. We predict that such changes will be particularly apparent in brain regions, and further, that these activation studies will predict cognitive decline earlier and more accurately than other measures, thereby facilitating the development of interventional therapies. As demonstrated in our preliminary data using fluoro-deoxyglucose PET(FDG-PET) as a crude marker of functional activation, we have shown clear evidence that activation studies can predict which individuals will suffer from the more rapid cognitive decline characteristic of AD. We have also developed a battery of neuropsychological tests sufficiently sensitive to changes in mental status that accurate indications of cognitive decline can be gathered in a two year period, thus making possible a longitudinal study of activation imaging. Our experience with fMRI has corroborated our expectation of improved sensitivity as compared to FDG-PET. We anticipate still further improvements in sensitivity as the new fMRI center becomes available at UCLA in Spring of 1995. This project will draw upon existing programs in Bran Mapping and early AD, an Alzheimer Disease Center (supported by the NIA), established multi-center collaborations in neurogenetics, and an available subject pool from 21 pedigrees with familial AD (410 living relatives [41 demented, 175 at- risk relatives, and 194 others]). The proposed activation studies of at- risk subjects also will elucidate pathophysiological mechanisms prior to confounding effects of disease chronicity. This research will provide the groundwork for future longitudinal studies using serial brain imaging that will determine the time course for progression of cerebral functional abnormalities, providing an objective and noninvasive means to monitor experimental therapeutic trials.